The Genome Project
What are the implications of a decoded human genome? Predict the
uses humankind will find for this knowledge.
"Scientists should think carefully before 'discovering' a
gene for IQ, sexuality, obesity, etc. Making these illnesses solidifies
discrimination, intolerant worldviews, and implies that we need to cure
people." &nbsp schm

"We will be able to see more clearly those things about us that are
nature and those that are nurture." &nbsp jashy

ASHINGTON, June 26 -- In an
achievement that represents a pinnacle of human self-knowledge, two
rival groups of scientists said today
that they had deciphered the hereditary script, the set of instructions
that defines the human organism.

"Today we are learning the language in which God created life,"
President Clinton said at a White
House ceremony attended by members of the two teams, Dr. James D.
Watson, co-discoverer of the structure of DNA, and, via satellite, Prime
Minister Tony Blair of Britain. [Excerpts, Page D8.]

The teams' leaders, Dr. J. Craig
Venter, president of Celera Genomics, and Dr. Francis S. Collins, director of the National Human Genome Research Institute, praised
each other's contributions and signaled a spirit of cooperation from
now on, even though the two efforts
will remain firmly independent.

The human genome, the ancient
script that has now been deciphered,
consists of two sets of 23 giant DNA
molecules, or chromosomes, with
each set -- one inherited from each
parent -- containing more than three
billion chemical units.

The successful deciphering of this
vast genetic archive attests to the
extraordinary pace of biology's advance since 1953, when the structure
of DNA was first discovered and
presages an era of even brisker
progress.

Understanding the human genome
is expected to revolutionize the practice of medicine. Biologists expect in
time to develop an array of diagnostics and treatments based on it and
tailored to individual patients, some
of which will exploit the body's own
mechanisms of self-repair.

The knowledge in the genome
could also be used in harmful ways,
particularly in revealing patients'
disposition to disease if their privacy
is not safeguarded, and in causing
discrimination.

The joint announcement is something of a shotgun marriage because
neither side's version of the human
genome is complete, nor do they
agree on the genome's size. Neither
has sequenced -- meaning to determine the order of the chemical subunits -- the DNA of certain short
structural regions of the genome,
which cannot yet be analyzed.

With the rest of the genome, which
contains the human genes and much
else, both sides' versions have many
small gaps, although these are
thought to contain few or no genes.
Today's versions are effectively
complete representations of the genome but leave much more work to
be done.

The two groups even differ on the
size of the gene-coding part of the
genome. Celera says it is 3.12 billion
letters of DNA; the public consortium that it is 3.15 billion units, a
letter difference of 30 million. Neither side can yet describe the genome's full size or determine the
number of human genes.

The public consortium has also
fallen somewhat behind in its goal of
attaining a working draft in which 90
percent of the gene-containing part
of the genome was sequenced. Its
version today has reached only 85
percent, suggesting it was marching
to Celera's timetable.

Today's announcement heralded
an unexpected truce between the two
groups of scientists who have been
racing to finish the genome. Veering
away from the prospect of asserting
rival claims of victory, the two chose
to report simultaneously their attainment of different milestones in their
quest.

Celera, a unit of the PE Corporation, has obtained its 3.12 billion letters of the genome in the form of long
continuous sequences, mostly about
2 million letters each, but with many
small gaps.

A less complete version has been
reported by the Human Genome
Project, a consortium of academic
centers supported largely by the National Institutes of Health and the
Wellcome Trust, a medical philanthropy in London.

Dr. Collins, the
consortium's leader, said its scientists had sequenced 85 percent of the
genome in a "working draft," meaning its accuracy will be upgraded
later.

Both versions of the human genome meet the important goal of
allowing scientists to search them
for desired genes, the genetic instructions encoded in the DNA. The
consortium's genome data is freely
available now. Celera has said it will
make a version of its genome sequence freely available at a later
date.

In their remarks at the White
House, Dr. Collins and Dr. Venter
both sought to capture the wider
meaning of their work in identifying
the eye-glazing stream of A's, G's,
C's and T's, the letters in the genome's four-letter code.

"We have caught the first
glimpses of our instruction book, previously known only to God," Dr. Collins said.

Dr. Venter spoke of his
conviction from seeing people die in
Vietnam, where he served as a medic, that the human spirit transcended
the physiology that is controlled by
the genome.

The two genome versions were obtained through prodigious efforts by
each side, involving skilled management of teams of scientists working
around the clock on a novel technological frontier.

Spurring their efforts was the glittering lure of the genome as a scientific prize, and a rivalry fueled by
personal differences and conflicting
agendas.

Dr. Venter, a genomics pioneer
whose innovative methods have at
times been scorned by experts in the
consortium's camp, has often cast
himself, not without reason, as an
outsider battling a hostile establishment.

The consortium scientists were
halfway through a successful 15-year
program to complete the human genome by 2005, when Dr. Venter announced in May 1998 that as head of a
new company, later called Celera, he
would beat them to their goal by 5
years.

His bombshell entry turned an academic pursuit into a fierce race. Dr.
Collins responded by moving his
completion date forward to 2003 and
setting this month as the target for a
90 percent draft.

"These folks have pulled out all the
stops," he said of his staff in an
interview last week. "They have
achieved a ramp-up that is beyond
anything one would have imagined
possible."

The 15-year cost of the Human
Genome Project, which began in
1990, has been estimated at $3 billion,
but includes many incidental expenses. The consortium has spent
only $300 million on sequencing the
human genome since January 1999,
when its all-out production phase began.

Celera has not released its
costs, but Dr. Venter said a year ago
that he expected Celera's human genome to cost $200 million to $250
million.

The race opened with mutual predictions of defeat. The consortium's
senior scientists predicted in December 1998 that Dr. Venter's method of
reassembling the sequenced fragments of genomic DNA was bound to
fail. In May 1999, Dr. Venter, confident of Celera's impending success,
observed that the National Institutes
of Health and the Wellcome Trust
were "putting good money after
bad."

The groups were divided by political as well as technical agendas. The
consortium's two principal scientists, Dr. John E. Sulston of the Sanger Center in England and Dr. Robert
Waterston of Washington University
in St. Louis, insisted that the genome
data should be published nightly, an
unusually generous policy because
scientists generally harvest new
data for their own discoveries before
sharing it.

Both of the consortium's administrative leaders, Dr. James D. Watson, and his successor, Dr. Collins,
made a point of seeking out international partners so that the rest of the
world would not feel excluded from
the genome triumph. Thus even
though centers in the United States
and Britain have done most of the
heavy lifting, important contributions to the consortium's genome
draft have been made by centers in
Germany, France, Japan and China.

Academic scientists have felt
some chagrin that an altruistic, open
and technically successful venture
like the Human Genome Project
should be upstaged by a commercial
rival financed by the company that
made the consortium's DNA sequencing machines.

But though Celera seeks to profit
by operating a genomic database,
Dr. Venter also believed that he
could make the genome and its benefits available a lot sooner. He has
succeeded in doing so, and in spurring the consortium to move faster.

Today's truce between the two
teams offers several advantages.
For Celera to claim victory over the
consortium would risk alienating
customers in the academic community. For the consortium, the surety
of opting into a draw now may have
seemed better than the risks of
claiming victory with a complete genome much later.

Celera's version of the genome depends on the consortium's data. And
the many small gaps in Celera's sequence will probably be filled by the
consortium's scientists, adding further to their claim on credit for the
final product.

The present truce between the
sides is limited to today's announcement and an agreement to publish
their reports in the same journal,
although the details remain to be
worked out. A joint workshop will be
held to discuss the genome versions.

The versions of the human genome
produced by the two teams are in
different states of completion because of the different methods each
used to determine the order of DNA
units in the genome.

The consortium chose first to
break the genome down into large
chunks, called BAC's, which are
about 150,000 DNA letters long, and
to sequence each BAC separately.
This BAC by BAC strategy also required "mapping" the genome, or
defining short sequences of milestone DNA that would help show
where each BAC belonged on its parent chromosome, the giant DNA molecules of which the genome is composed.

BAC's are assembled from thousands of snippets of DNA, each about
500 DNA letters in length. This is the
longest run of DNA letters that the
DNA sequencing machines can analyze.

A computer pieces together the
snippets by looking for matches in
the DNA sequence where one snippet
overlaps another.

But the BAC's do not assemble
cleanly from their component snippets. One reason is that human DNA
is full of repetitive sequences -- the
same run of letters repeated over
and over again -- and these repetitions baffle the computer algorithms
set to assemble the pieces.

The stage the consortium has now
reached is that all its BAC's are
mapped, making the whole genome
available in a nested set of smaller
jigsaw puzzles.

But the BAC's are in
varying stages of completion. The
BAC's covering the two smallest human chromosomes, numbers 21 and
22, are essentially complete. But
many other BAC's are in less immaculate states of assembly. Many
consist of assembled pieces no more
than 10,000 units long, and the order
of these pieces within each BAC is
not known.

The sum of the assembled pieces
in each BAC now covers 85 percent of
the genome. This working draft, as
the consortium calls it, is maybe not
a thing of beauty but is of great value
to researchers looking for genes and
represents a major accomplishment.

Celera's genome has been assembled by a different method, called a
whole genome shotgun strategy.

Following a scheme proposed by Dr.
Eugene Myers and Dr. J. L. Weber,
Celera skips the time-consuming
mapping stage and breaks the whole
genome down into a set of fragments
that are 2,000, 10,000 and 50,000 letters long. These fragments are analyzed separately and then assembled
in a single mammoth computer run,
with a handful of clever tricks to step
across the repetitive sequence regions in the DNA.

The approach ideally required sequencing 30 billions units of DNA --
10 times that in a single genome.

Dr.
Venter seems to have taken a considerable risk by starting his assembly
at the end of March this year when
he possessed only a threefold coverage of the genome. He has since
raised his total to 4.6-fold coverage.

The decision may have been influenced by Celera's rate of capital
expenditure -- the company's electric bill alone is $100,000 a month --
and by the need to sequence the
mouse genome as well so as to offer
database clients a two-genome package.

The mouse genome is expected
to be invaluable for interpreting the
human genome, and Dr. Venter said
today that Celera would finish sequencing it by the end of the year.

Because of having relatively little
of its own data, Celera made use of
the consortium's publicly available
sequence data and, indirectly, of the
positional information contained in
the consortium's mapped set of
BAC's. The consortium can justifiably share in the credit for Celera's
version of the genome, another cogent factor in the logic of today's
truce.

Biotech Shares Rise and Fall

Stocks of biotechnology companies
rose early yesterday after a White
House announcement that the first
survey of the human genome had
been completed, but investors
cashed in some of their profits before
trading ended, causing several issues to fall.

Biotechnology shares peaked in
March in a speculative frenzy, before backsliding sharply. In recent
weeks, they again posted significant
increases in anticipation of the genome announcement.

The Celera Genomics unit of the
PE Corporation, which participated
in the mapping project and has been
one of the highest fliers, dropped
$12.25, to $113 yesterday. The stock of
the company, based in Rockville,
Md., hit a record high of $252 a share
on Feb. 25. Although well off its high,
Celera shares are still up 1,400 percent from this time last year.